Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy

Chen, Min Yu; Liao, Warren S.L.; Lü, Zhen; Bornmann, William G.; Hennessey, Violeta; Washington, Michele N.; Rosner, Gary L.; Yu, Yinhua; Ahmed, Ahmed A.; Bast, Robert C.

doi:10.1002/cncr.26073

Cited by 126 publications

(101 citation statements)

References 36 publications

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“…36 In addition to ovarian cancer, downregulation of ARHI has been associated with cancers at other sites, including breast, prostate, pancreatic, thyroid and lung carcinomas. 4,[37][38][39][40][41][42][43][44][45][46] Consequently, the observations made in ovarian cancer are likely to be relevant to many other types of cancer. In the future, it will be of interest to explore the interaction of ARHI and FOXo3a across cancers that originate from non-ovarian sites.…”

Section: Discussionmentioning

confidence: 99%

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

Lü¹,

Yang

Sutton

et al. 2014

Cell Death Differ

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The process of autophagy has been described in detail at the molecular level in normal cells, but less is known of its regulation in cancer cells. Aplasia Ras homolog member I (ARHI; DIRAS3) is an imprinted tumor suppressor gene that is downregulated in multiple malignancies including ovarian cancer. Re-expression of ARHI slows proliferation, inhibits motility, induces autophagy and produces tumor dormancy. Our previous studies have implicated autophagy in the survival of dormant ovarian cancer cells and have shown that ARHI is required for autophagy induced by starvation or rapamycin treatment. Re-expression of ARHI in ovarian cancer cells blocks signaling through the PI3K and Ras/MAP pathways, which, in turn, downregulates mTOR and initiates autophagy. Here we show that ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. ARHImediated downregulation of PI3K/AKT and Ras/ERK signaling also decreases phosphorylation of FOXo3a, which sequesters this transcription factor in the nucleus. Nuclear retention of FOXo3a induces ATG4 and MAP-LC3-I, required for maturation of autophagosomes, and also increases the expression of Rab7, required for fusion of autophagosomes with lysosomes. Following the knockdown of FOXo3a or Rab7, autophagolysosome formation was observed but was markedly inhibited, resulting in numerous enlarged autophagosomes. ARHI expression correlates with LC3 expression and FOXo3a nuclear localization in surgical specimens of ovarian cancer. Thus, ARHI contributes to the induction of autophagy through multiple mechanisms in ovarian cancer cells. Autophagy is a dynamic intracellular process that degrades organelles and long-lived cytosolic proteins by sequestration within double-membrane enclosed vesicles termed autophagosomes. Lysosomes fuse with autophagosomes to produce autolysosome. Within acidified autolysosome, hydrolases cleave proteins and lipids, releasing amino acids and fatty acids that can provide energy for cells in a nutrient-poor environment.1,2 While many of the steps involved in autophagy have been well described at a molecular level, regulation of these events in malignant mammalian cells is less well understood.Our group has identified a maternally imprinted tumor suppressor gene, DIRAS3, which regulates several steps in autophagy including induction and membrane elongation. Aplasia Ras homolog member I (ARHI) is an imprinted gene that is expressed from a single paternal allele in most normal tissues and that is downregulated in a fraction of carcinomas of the ovary, breast, lung, prostate, thyroid and pancreas. ARHI's downregulation in 460% of ovarian cancers is associated with decreased progression-free survival.3 Downregulation is achieved through multiple mechanisms, including loss of heterozygosity, DNA methylation, transcriptional regulation and shortened RNA half-life.4-14 ARHI encodes a 26 kDa GTPase with 50-60% homology to Ras and...

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Section: Discussionmentioning

confidence: 99%

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

Lü¹,

Yang

Sutton

et al. 2014

Cell Death Differ

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“…Although Ume6 is not conserved in mammalian cells, the regulation of the FOXO family by Sch9 and AKT1 suggests that the pathway regulating Atg8/LC3 may be conserved from yeast to human. Just as the knockdown of SIN3A and SIN3B promotes an increase in cellular LC3 levels, inhibition of RPD3 promotes a similar increase (29)(30)(31), although the detailed mechanism has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Bartholomew

Suzuki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

123

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Autophagy has been implicated in a number of physiological processes important for human heath and disease. Autophagy involves the formation of a double-membrane cytosolic vesicle, an autophagosome. Central to the formation of the autophagosome is the ubiquitin-like protein autophagy-related (Atg)8 (microtubuleassociated protein 1 light chain 3/LC3 in mammalian cells). Following autophagy induction, Atg8 shows the greatest change in expression of any of the proteins required for autophagy. The magnitude of autophagy is, in part, controlled by the amount of Atg8; thus, controlling Atg8 protein levels is one potential mechanism for modulating autophagy activity. We have identified a negative regulator of ATG8 transcription, Ume6, which acts along with a histone deacetylase complex including Sin3 and Rpd3 to regulate Atg8 levels; deletion of any of these components leads to an increase in Atg8 and a concomitant increase in autophagic activity. A similar regulatory mechanism is present in mammalian cells, indicating that this process is highly conserved.lysosome | membrane biogenesis | phagophore | stress | vacuole M acroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved process used by eukaryotic cells for the bulk degradation of intracellular proteins and organelles (1). Autophagy is not only vital for cell survival in nutrient-poor conditions (2) but is also linked to various physiological processes, including immune defense, tumor suppression, and prevention of neurodegeneration (3). Whereas autophagy plays a primarily protective role, it can also contribute to cell death; thus, the magnitude of autophagy must be carefully regulated.Central to autophagy is the formation of autophagosomes (4), double-membrane-bound structures that engulf and deliver cytoplasmic materials to the vacuole/lysosome for degradation. During autophagosome formation, the autophagy-related ubiquitin-like protein Atg8/microtubule-associated protein 1 light chain 3 (LC3) covalently modifies phosphatidylethanolamine (PE). Almost one-fourth of the characterized autophagy-related (Atg) proteins in yeast are involved in the formation or stability of Atg8-PE, which plays a critical role in controlling expansion of the phagophore (the initial sequestering membrane), and in determining autophagosome size, thereby regulating autophagy activity (5, 6). Upon starvation, the level of ATG8 mRNA sharply increases, leading to a subsequent induction of the Atg8 protein level (7,8). The increase in the amount of Atg8 during autophagy is critical for supplying a sufficient amount of this protein to maintain normal levels of autophagy; yeast strains deficient in Atg8 induction generate abnormally small autophagosomes (5). Thus, characterization of how Atg8 protein levels are modulated is of tremendous importance both in understanding the regulation of autophagy and for the elucidation of potential therapeutic targets. However, little is known about the mechanisms regulating ATG8 transcription. ResultsUme6-Sin3-Rpd3 Complex Represse...

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“…Vorinostat and romidepsin have both been approved by the FDA for the treatment of cutaneous T‐cell lymphoma. Both agents, in combination with cytotoxic agents, have shown significant activity in inhibiting ovarian cancer cell growth in preclinical studies 118, 119, 120. However, in a phase II study, vorinostat displayed minimal activity as a single agent for treating persistent or recurrent epithelial ovarian or primary peritoneal carcinoma, despite its acceptable tolerability 121.…”

Section: Molecular Targeted Treatmentmentioning

confidence: 99%

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

Bai

Cao

Yang

et al. 2016

J Cellular Molecular Medi

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Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and tumoural heterogeneity (TH) has been blamed for treatment failure. The genomic and epigenomic atlas of EOC varies significantly with tumour histotype, grade, stage, sensitivity to chemotherapy and prognosis. Rapidly accumulating knowledge about the genetic and epigenetic events that control TH in EOC has facilitated the development of molecular‐targeted therapy. Poly (ADP‐ribose) polymerase (PARP) inhibitors, designed to target homologous recombination, are poised to change how breast cancer susceptibility gene (BRCA)‐related ovarian cancer is treated. Epigenetic treatment regimens being tested in clinical or preclinical studies could provide promising novel treatment approaches and hope for improving patient survival.

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Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest, and autophagy

Cited by 126 publications

References 36 publications

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

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